ARTICLE
Revisiting Cardiopulmonary Exercise Testing Applications in Heart Failure: Aligning Evidence with Clinical Practice Ross Arena 1, Marco Guazzi 2, Lawrence P. Cahalin 3, and Jonathan Myers 4 1
Department of Physical Therapy and Integrative Physiology Laboratory, College of Applied Health Sciences, University of Illinois Chicago, Chicago, IL; 2Heart Failure Unit, Cardiology, University of Milano, IRCCS Policlinico San Donato, Milano, Italy; 3Department of Physical Therapy, Leonard M. Miller School of Medicine, University of Miami, Miami, FL; and 4Division of Cardiology, VA Palo Alto Healthcare System, Palo Alto, CA. ARENA, R., M. GUAZZI, L.P. CAHALIN, and J. MYERS. Revisiting cardiopulmonary exercise testing applications in heart failure: aligning evidence with clinical practice. Exerc. Sport Sci. Rev., Vol. 42, No. 4, pp. 153Y160, 2014. American Heart Association/ American College of Cardiology class recommendations and associated level of evidence for cardiopulmonary exercise testing (CPX) have been put forth. A new paradigm is proposed for CPX use and interpretation in heart failure (HF). Evidence for this new paradigm will be provided, showing that clinical utilization, class recommendations, and the associated level of evidence for CPX in the HF population can be expanded significantly. Key Words: exercise testing, expired gas, prognosis, diagnosis, class recommendation, level of evidence
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plantation.’’ There was no associated level of evidence with this recommendation (19,20). The more recent HF-specific clinical guideline (2005 and 2009 update) changed the recommendation for CPX to Class IIa (i.e., ‘‘indicates that the weight of evidence/opinion is in favor of usefulness/efficacy’’) as ‘‘being reasonable to identify high-risk patients presenting with HF who are candidates for cardiac transplantation or other advanced treatments’’ (32). The level of evidence associated with this recommendation was ‘‘B’’ (i.e., ‘‘a limited number of randomized controlled trials with small numbers of studies or observational registries’’). No rationale was provided for the change in CPX class recommendation (i.e., from I to IIa). Despite the change in class recommendation, CPX utilization in patients with HF has been viewed, at least in concept, as a widely available clinical standard of care for more than a decade (15). There are several caveats to previous CPX class recommendation and level of evidence designations that may not be readily apparent: 1) The reason CPX continues to be considered valuable in patients with HF who are being considered for heart transplantation or other advanced treatments is because of the assumption that this procedure provides a robust ability to predict adverse events, in particular, mortality. During the last decade, the value of CPX in predicting mortality in HF has been confirmed consistently by numerous observational studies, even in cohorts not being considered for transplantation or other advanced treatments. However, the view of the prognostic and, therefore, primary
INTRODUCTION The American Heart Association (AHA) and the American College of Cardiology (ACC) use a rigorous system for determining class recommendation and associated level of evidence for practice patterns, serving as the basis for their clinical guidelines. A detailed description of this system is provided elsewhere (21). The AHA/ACC has used this class recommendation/level of evidence system for the use of cardiopulmonary exercise testing (CPX) in patients with heart failure (HF). Initial guidance (1997 and 2002 update) afforded CPX a Class I recommendation (i.e., ‘‘conditions for which there is evidence or general agreement that a given procedure or treatment is useful and effective’’) for the ‘‘evaluation of exercise capacity and response to therapy in patients with HF who are being considered for heart trans-
Address for correspondence: Ross Arena, Ph.D., P.T., FAHA, Department of Physical Therapy, College of Applied Health Sciences, University of Illinois Chicago, 1919 W. Taylor St. (MC 898), Chicago, IL 60612 (E-mail: [email protected]). Accepted for publication: May 5, 2014. Associate Editor: Bo Fernhall, Ph.D., FACSM 0091-6331/4204/153Y160 Exercise and Sport Sciences Reviews Copyright * 2014 by the American College of Sports Medicine
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clinical utility of CPX remains narrowly focused on those being considered for end-stage interventions (e.g., transplantation); 2) In both previous AHA/ACC clinical practice guidelines and their revisions, peak oxygen consumption ˙ O2) was the only variable considered for the assessment of (V transplant candidacy, advanced treatments, or gauging therapeutic efficacy V despite the fact that a host of other potentially valuable CPX variables are readily obtainable; and 3) Given that heart transplantation continues to be reserved for patients diagnosed as having HF and reduced ejection fraction (HFrEF), the recommendations provided in these clinical guidelines were meant to apply exclusively to this subgroup. Thus, none of the CPX proposed recommendations provided in these guidelines apply to patients with HF and preserved ejection fraction (HFpEF). The body of scientific evidence and perceived clinical utility and value of CPX currently are incongruent. Stated succinctly, previous clinical practice ˙ O2 is the guidelines perpetuate the following premise: Peak V only CPX variable that holds prognostic value, only in patients with HFrEF. Scientific evidence, however, indicates that the value and clinical applications of CPX in the HF population are much richer and broader, respectively. There have been many advances in the years since the 1997 and 2002 updates to the AHA/ACC Guidelines for Exercise Testing were published (19,20). The same can be said for the 2005 and 2009 updates to the guidelines for HF diagnosis and management (32). The clinical, pharmacologic, and surgical management of the HF population continues to expand and evolve, and, although prognosis in this chronic disease population remains disconcerting, it has improved substantially. Moreover, the unique pathophysiology, presentation, and clinical trajectory of patients diagnosed with HFrEF as compared with those with HFpEF are being recognized increasingly. Lastly, the body of evidence investigating the clinical utility of CPX with respect to prognostic, diagnostic, and therapeutic efficacy assessments continues to increase. As such, a new paradigm for CPX use and interpretation in HF is warranted. We hypothesize that scientific evidence for this new paradigm is substantial, proving that clinical utilization, class recommendations, and the associated level of evidence for CPX in the HF population can be expanded significantly. Our group initiated a multicenter consortium in 2002 in an effort to gain better insights into the role of CPX in HF. Combining data from established centers allow important hypotheses to be tested with an appropriate sample size (currently n 9 2500) and, thus, statistical power (36). The multicenter consortium has contributed significantly to the worldwide body of work related to CPX utility in HF (22). The collective body of available evidence supports the hypothesis that a new CPX paradigm is warranted, one that involves: 1) expanding the list of relevant CPX variables based on scientific evidence; 2) incorporating diagnostic, prognostic, and therapeutic efficacy applications; and 3) expanding utilization of CPX beyond patients with HFrEF being considered for heart transplantation. Many of the studies discussed in subsequent sections of this article focus on results from the multicenter consortium, lending support to the hypothesis that a new CPX paradigm in HF is justifiable. Updated/revised/expanded class 154 Exercise and Sport Sciences Reviews
recommendations and associated levels of evidence will be presented with the following questions in mind: 1) Does CPX continue to provide prognostic value in patients with HF? 2) Would there be value to expanding the clinical applications of CPX to all patients with HF, as opposed to only those being evaluated actively for transplantation? 3) Should the list of CPX variables for prognostic assessment be expanded ˙ O2? 4) Are key CPX variables responsive to beyond peak V various interventions, allowing for a valid and reliable gauge of therapeutic efficacy? 5) What CPX variables(s) should be included in the assessment of therapeutic efficacy? 6) Are there diagnostic applications for CPX in patients with HF? and 7) Should CPX be used clinically in both the HFrEF and HFpEF populations?
CURRENT APPRAISAL OF THE PROGNOSTIC VALUE OF CPX In 1991, Mancini et al. (34) published their seminal work ˙ O2 in a group of 114 patients on the predictive value of peak V with HFrEF, demonstrating its significant prognostic ability. Since that time and for reasons that are not clear, a narrow and limited clinical view of the prognostic value of CPX perpetuates, despite the fact that evidence continues to mount in support of a new broader paradigm. The multicenter consortium has published a number of analyses related to the prognostic value of CPX, supporting the hypothesis that a new broader prognostic paradigm is warranted. The consortium’s work reaffirms the prognostic ˙ O2 as well as significantly contributes to the value of peak V rationale of expanding the prognostic assessment to other CPX variables based on sound physiologic rationale for why they may be relevant clinically. There is a specific interest in ventilatory efficiency, in particular, expressed as the minute ventilation per carbon dioxide production (VE/VCO2) slope. The multicenter consortium demonstrated that the VE/VCO2 slope portended an optimal prognostic value when all exercise testing data are used (i.e., from the initiation of the CPX to the attainment of maximal effort) (6), a finding subsequently supported by other research groups. A number of other consortium publications demonstrate that both the VE/VCO2 ˙ O2 are robust prognostic markers in patients slope and peak V ˙ O2 with HFrEF (1,3,8,9,12). However, although both peak V and the VE/VCO2 slope are significant prognostically, the latter is more robust in univariate analyses (3,7,8,16), a finding also supported by other research groups. However, both variables oftentimes remain significant prognostically in a multivariate model. In 2007, the consortium introduced a ventilatory classification system based on the VE/VCO2 slope (3). During the same period, the emergence of the beta-blocker era and ˙ O2 with a concomitant improveits neutral impact on peak V ment in survival precipitated reconsideration of the less than or equal to/greater than 14 mLO2&kgj1&minj1 prognostic threshold. Indeed, a threshold of less than/greater than or equal to 10 mLO2&kgj1&minj1 was suggested to be more appropriate in HFrEF patients prescribed a beta-blocker (37). With respect to the VE/VCO2 slope, it seemed that patients with a value greater than or equal to 45 (normal value G30) had a particularly poor prognosis (3). As the body of literature evolved, it www.acsm-essr.org
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was proposed that patients with a VE/VCO2 slope greater than ˙ O2 less than 10 mLO2&kgj1&minj1 or equal to 45 and peak V had a particularly poor prognosis and should be considered to be at extremely high risk for adverse events (i.e., estimated to be 950%) (14). Moreover, for HFrEF patients with a VE/ ˙ O2 below and above these ominous VCO2 slope and peak V thresholds, respectively, prognostic outlook improved progressively, with a multilevel model being the best approach to risk assessment. For patients with a VE/VCO2 slope less than 30 ˙ O2 greater than 20 mlO2&kgj1&minj1, prognosis is and peak V considered excellent, at least during the next 2 to 4 yr. This was the beginning of an expanded view of CPX variables for prognostic analysis and a new paradigm, combining the VE/ ˙ O2 response. VCO2 slope and the peak V Further growth of the multicenter HF consortium CPX database prompted exploration of the additive prognostic value of other CPX variables; both those obtained from ventilatory expired gas and traditional monitoring (i.e., heart rate, blood pressure, and subjective symptoms), further evolving the new paradigm. Exercise oscillatory ventilation (EOV) (26), the partial pressure of end-tidal CO2 (PETCO2) at rest and during exercise (10,13), heart rate recovery (HRR) (4,11), and dyspnea as a test termination criteria (18) are all prognostically significant in patients with HF, supporting the hypothesis that an expanding prognostic CPX paradigm portends an improved three-dimensional resolution in predicting adverse events. The demonstrated prognostic ability of all aforementioned CPX variables is grounded in the fact that each provides a unique reflection of the degree of pathophysiology present in one or more of the systems influencing the response to aerobic exercise (i.e., pulmonary/respiratory, cardiovascular, skeletal muscle). A discussion of the link between CPX measures and pathophysiology is beyond the scope of this article; other excellent resources addressing this issue are available (15). The multicenter consortium recently proposed a CPX score incorporating the majority of these variables (35), which was validated recently in a subsequent publication (36). Other research groups that have assessed large HF cohorts have demonstrated similar findings regarding the prognostic value of the aforementioned CPX variables. In 2012, the AHA and European Association for Cardiovascular Prevention and Rehabilitation jointly published the Clinical Recommendations for Cardiopulmonary Exercise Testing Data Assessment for Specific Patient Populations, including HF (22). This joint statement recommends that the VE/VCO2 ˙ O2, EOV, PETCO2, systolic blood pressure reslope, peak V sponse, exercise electrocardiography, HRR, and subjective symptom exercise termination criteria be assessed collectively for a more refined prognostic assessment. This color-coded prognostic model is illustrated in the Figure. This new paradigm represents the current best-practice recommendation for the interpretation of CPX data for prognostic purposes in the HF population. This new paradigm is supported strongly by evidence, reflecting a body of literature that collectively has assessed the prognostic value of CPX in thousands of patients with HF, with strong consistency in findings among the different research groups around the world. As such, we feel that the evidence-based model illustrated in the Figure is an excellent example of the vision for a new CPX paradigm that this article has set out to propose. Volume 42 & Number 4 & October 2014
CPX AS A GAUGE FOR THERAPEUTIC EFFICACY Although the original AHA/ACC Guidelines for Exercise Testing also afforded CPX a Class I recommendation to gauge the ‘‘response to therapy in patients with HF who are being considered for heart transplantation,’’ its use in this capacity is not commonplace clinically. This approach entails serial CPX testing before and after the implementation of a given intervention. Use of CPX as a gauge for therapeutic efficacy aligns with the prognostic applications previously described; if a given intervention improves the CPX response, it is reasonable to hypothesize that prognosis likewise improves. Given the robust prognostic value of CPX, in particular using the newly proposed multivariable paradigm illustrated in the Figure, assessing the change in key variables after the initiation or titration of a given intervention potentially would be of high value in guiding clinical management. The concept of serial CPX was reinforced in the 2007 multicenter consortium paper introducing the Ventilatory Classification System (3). Specifically, in patients with an abnormal VE/VCO2 slope, reviewing and titrating medical management are recommended. When medical management is titrated, repeating CPX to assess therapeutic efficacy is proposed. Other publications have demonstrated significant improvements in key CPX variables, most notably the VE/VCO2 slope and peak ˙ O2, after numerous intervention strategies (23). Moreover, V a reduction in pulmonary artery pressure after treatment with sildenafil, a phosphodiesterase 5 inhibitor, significantly correlates with the reduction in the VE/VCO2 slope (25). It also seems that treatment with sildenafil reverses EOV (31). In addition, an interleukin 1 receptor antagonist trial initially ˙ O2 has demonstrated significant improvements in peak V and the VE/VCO2 slope in patients with HFrEF after this pharmacologic intervention (38). These studies convincingly demonstrate that CPX is a valuable tool in indentifying responders versus nonresponders to a given therapeutic intervention, recalibrating prognostic outlook based on therapeutic responsiveness, and further titrating clinical management based on the level of responsiveness as reflected by the change in CPX. Physiologic mechanisms for the improvement in CPX variables are based uniquely on a specific therapeutic intervention (e.g., the reduction in the VE/VCO2 slope with sildenafil is related to the concomitant reduction in pulmonary pressure and subsequent improvement in ventilation-perfusion matching). In conclusion, the research findings described in this section support the premise that multiple CPX variables respond favorably to interventions that have a positive physiologic impact on the cardiovascular and/or pulmonary systems. Thus, assessing therapeutic CPX improvements through the new multivariate paradigm illustrated in the Figure is warranted.
THE DIAGNOSTIC APPLICATIONS OF CPX The diagnostic applications of CPX in patients with HF previously have not been afforded a class recommendation and associated level of evidence designation in the AHA/ ACC clinical practice guidelines. Admittedly, CPX as a tool to determine an initial diagnosis of HF would not be warranted because a number of other chronic conditions produce CPX in Heart Failure
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Figure. Clinical CPX stratification for patients with HF. (Reprinted from (22). Copyright * 2012 American Heart Association. Used with permission.) *Peak V˙O2 valid if peak RER is Q1.00 or test terminated secondary to abnormal hemodynamic or ECG exercise response. VE/VCO2 indicates minute ventilation/carbon dioxide production; V˙O2, oxygen consumption; EOV, exercise oscillatory ventilation; PETCO2, partial pressure of end-tidal carbon dioxide; ET, exercise test; ECG, electrocardiogram; HRR, heart rate recovery; BP, blood pressure; CPX, cardiopulmonary exercise testing; HF, heart failure; PH, pulmonary hypertension; RER, respiratory exchange ratio.
similar CPX abnormalities (e.g., pulmonary arterial hypertension, congenital heart defects, and interstitial lung disease). However, the use of CPX to aid in the diagnosis of secondary pathophysiologic consequences of HF seems appropriate and clinically valuable, in particular, left-sided pulmonary hypertension (PH) (28). Ventilatory inefficiency, as expressed by an elevated VE/VCO2 slope, possesses the ability to diagnose left-sided PH noninvasively with acceptable sensitivity/specificity and positive/negative predictive values. 156 Exercise and Sport Sciences Reviews
The pathophysiologic rationale for this relationship is the fact that increased pulmonary pressure creates a greater ventilationperfusion mismatch, reflected by an elevated VE/VCO2 slope. Moreover, there seems to be a significant correlation between the severity of PH (i.e., degree of rise in pulmonary artery pressure) and the degree of elevation in the VE/VCO2 slope; thus, the latter seems to provide a noninvasive reflection of disease severity. As described in the review by Arena et al. (2), the majority of the literature supporting this premise has been www.acsm-essr.org
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performed in cohorts diagnosed as having primary pulmonary vascular disease. However, Guazzi et al. recently demonstrated that the VE/VCO2 slope (threshold G/Q36, odds ratio = 12.1, P G 0.001) was the strongest predictor of an elevated pulmonary artery systolic pressure (Q40 mmHg), assessed by Doppler echocardiography, in an HF cohort (n = 293). Peak exercise PETCO2 (threshold e/936 mmHg, odds ratio = 3.8, P G 0.001) and EOV (yes vs. no, odds ratio = 3.2, P G 0.001), CPX variables that also reflect ventilatory inefficiency, improved the ability to detect an elevated pulmonary artery systolic pressure (odds ratio for all three variables combined = 16.7, P G 0.001). Thus, although CPX is not viewed as an assessment that holds value in confirming an HF diagnosis, it does hold value in diagnosing secondary consequences of HF, namely, left-sided PH. Moreover, although CPX is valuable in accurately detecting left-sided PH, the authors of this review do not recommend it should be viewed as the test that would confirm such a diagnosis. Rather, if the CPX response is strongly suggestive of left-sided PH in patients with HF (i.e., indicators of ventilatory efficiency), an appropriate next step would be to consider a follow-up assessment to confirm the initial impression, such as Doppler echocardiography or right heart catheterization.
UNIQUE CONSIDERATIONS FOR THE APPLICATION OF CPX IN HF As discussed in the Introduction, a primary and currently underexamined issue related to this focus is exploring the clinical value of CPX in patients diagnosed as having HFpEF. The multicenter consortium has examined the value of CPX in patients diagnosed as having HFpEF, supporting key facets of the newly proposed paradigm by demonstrating 1) a significant correlation between key CPX variables (i.e., peak ˙ O2, the VE/VCO2 slope, resting and exercise PETCO2) and V diastolic dysfunction, as assessed by Doppler echocardiography (i.e., E/E¶) (24); and 2) the prognostic significance of the
VE/VCO2 slope and EOV in patients with HFpEF (29,30). The multicenter consortium also has addressed other unique considerations in the CPX-HF literature, demonstrating 1) an interplay between the obesity paradox and the preserved ˙ O2 and the VE/VCO2 slope prognostic value of peak V (17,33); 2) the preserved prognostic value of CPX irrespective of both sex (27) and HF etiology (12); and 3) a 2- to 4-yr ˙ O2 and the VE/ window for the prognostic validity of peak V VCO2 slope, after which time a repeat assessment may be warranted (5).
CPX CLASS RECOMMENDATIONS AND ASSOCIATED LEVELS OF EVIDENCE It has been several years since the AHA/ACC class recommendations and associated levels of evidence have been reviewed for CPX in HF. Initially, CPX was afforded a Class I recommendation with no associated level of evidence in the AHA/ACC Guidelines for Exercise Testing (19). Moreover, the scope of the recommendation was rather narrow with respect to CPX variables assessed and the type of HF patients undergoing CPX (i.e., heart transplant candidates and HFrEF). The 2005 guidelines for the diagnosis and management of HF in adults revisited recommendations for CPX; changing the recommendation to Class IIa with an associated ‘‘B’’ level of evidence. To our knowledge, no rationale, evidence based or otherwise, was provided for this change in recommendation class. During this same time, the body of CPX literature has expanded exponentially, warranting reexamination of this issue. Our current assessment of this area allowed for several key observations to be made as a part of our newly proposed paradigm: 1) The AHA/ACC Class Recommendation/Level of Evidence System does not have language that describes specifically how to provide recommendations for or rate levels of evidence related to prognostic assessments; 2) The CPX body of literature in HF has expanded to a point where a more refined and detailed approach to class recommendation
TABLE 1. Broad language and concept guidance for CPX class recommendations. Class I
Class IIa
Class IIb
Class III
CPX is clearly prognostic/diagnostic
CPX is likely prognostic/diagnostic
CPX may be prognostic/diagnostic
CPX is not prognostic/diagnostic
CPX clearly gauges therapeutic efficacy
CPX likely gauges therapeutic efficacy
CPX may gauge therapeutic efficacy
CPX does not gauge therapeutic efficacy
CPX:
CPX:
CPX:
CPX:
- Should be performed
- Is probably recommended
- May be considered
- Has no benefit
- Is recommended
- Is probably indicated
- May be reasonable
- Is not recommended
- Is indicated
- Can be useful
- Usefulness is unknown
- Is not indicated
- Is useful
- Can be effective
- Usefulness is unclear
- Should not be performed
- Is effective
- Can be beneficial
- Usefulness is uncertain
- Should not be administered
- Is beneficial
- Usefulness is not well established
- Is not useful - Is not beneficial - Is not effective
CPX indicates cardiopulmonary exercise testing. Volume 42 & Number 4 & October 2014
CPX in Heart Failure
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TABLE 2. Broad language and concept guidance for CPX level of evidence ratings. Study Characteristics Level A
Study Findings
- Multiple investigations, possibly one or more meta-analyses
Results from overall body of evidence and meta-analyses (if available) consistently demonstrate similar findings.
- Prospective design
Sum of results from all studies allow for definitive conclusions without the need for further inquiry.
- Hard end point (mortality) collected in standardized and rigorous fashion for prognostic studies - Interventional trials using CPX as an end point used randomized controlled design - Recognized gold standard used as CPX comparator for diagnostic studies - Prognostic, interventional, and diagnostic studies consistently demonstrate rigorous research design, appropriate statistical tests, and sufficiently powered Level B
- Several investigations; total number of studies not considered definitive because of total number and/or study quality
Results from overall body of evidence may not consistently demonstrate similar findings. Sum of results from all studies do not allow for definitive conclusion, and further inquiry is needed.
- Mix of prospective and retrospective study designs - Mix of hard end point (i.e., mortality) and softer end point (i.e., hospitalization) collected in standardized but less rigorous fashion for prognostic studies - Interventional trials using CPX as an end point used mix of case control, cohort, and randomized controlled designs - CPX comparator for diagnostic studies not always been recognized gold standard - Prognostic, interventional, and diagnostic studies may present with limitations in research design rigor, appropriate statistical tests, and/or sufficient power Level C
- Scientific evidence, if any available, limited - Rely on consensus opinion of experts
Results from body of evidence, if available, not sufficient to draw any conclusions on consistency of findings. Studies from other areas may be used to derive expert opinion. Significant further inquiry is needed.
CPX indicates cardiopulmonary exercise testing.
and associated level of evidence is justified. These observations serve as the genesis of the new conceptual framework provided in Tables 1 to 3. Tables 1 and 2 provide guidance on class recommendation and levels of evidence language and concepts. These tables are constructed with the intent of being applicable to all areas relevant to CPX (i.e., prognosis, therapeutic efficacy, and diagnosis). The language and concepts presented in Tables 1 and 2 form the basis for the proposed CPX class recommendations and associated levels of evidence for prognostic, therapeutic efficacy, and diagnostic applications in the HF population, which are listed in Table 3. Based on the body of literature, the number of CPX variables that should be considered, the variation in how extensively each individual variable has been studied currently, and the number of potential CPX indications in the clinical and research settings, a more refined and extensive list of class recommendations and levels of evidence is ˙ O2, the VE/ warranted. With respect to prognosis, peak V VCO2 slope, and EOV are primary CPX markers with clear predictive values. Other variables add predictive values, and thus, a multivariate predictive model is appropriate. These recommendations are well established in patients with HFrEF. Initial prognostic analyses of CPX in patients with HFpEF 158 Exercise and Sport Sciences Reviews
shows promise but is more guarded, given that more research ˙ O2 are is needed in this area. The VE/VCO2 slope and peak V primary variables for gauging therapeutic efficacy, a premise well supported by the literature in patients with HFrEF. There also are some indications that reversal of EOV may occur with certain therapeutic interventions in patients with HFrEF, highlighting the important role this prognostic marker seems to have in clinical practice. In general, however, the use of CPX to gauge therapeutic efficacy in patients with HFpEF needs further inquiry. Lastly, the diagnostic utility of CPX may be useful in the overall HF population, in particular, the ability of abnormalities in ventilatory efficiency to detect leftsided PH. Additional research is needed to solidify the diagnostic value of CPX in HF.
CONCLUSIONS The current concept paper set out to test the hypothesis that a new and expanded paradigm for CPX application and interpretation in HF is warranted. The current body of research, significantly contributing to by the multicenter consortium, supports this paradigm. Clinical guidelines published www.acsm-essr.org
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TABLE 3. Class recommendation and level of evidence for CPX in heart failure. Recommendation
Classification
Level of Evidence
Class I
A
Secondary CPX variables, including PETCO2, ECG, systolic blood pressure, and the ECG response to exercise, are additional predictors of adverse events and can be useful during the prognostic assessment in patients with HFrEF. A resting PETCO2 G33 mmHg, a rise in PETCO2 G3 mmHg during exercise, a drop in systolic blood pressure during exercise, and/or ECG abnormalities warranting termination of exercise indicate a worse prognosis.
Class IIa
B
Use of a multivariate model composed of key CPX variables and thresholds, as illustrated in the Figure, can be useful in improving prognostic resolution in patients with HFrEF in comparison with variables assessed independently.
Class IIa
B
The prognostic value of patients with HFpEF is showing initial promise, in particular, the VE/VCO2 slope, ˙ O2, and EOV. These variables can be useful in providing prognostic information in patients with HFpEF. peak V
Class IIa
B
Use of a multivariate model composed of key CPX variables and thresholds, as illustrated in the Figure, can be useful in improving prognostic resolution in patients with HFpEF in comparison with variables assessed independently.
Class IIa
C
Class I
A
Reversal of EOV also may occur with pharmacologic, surgical, and exercise interventions in patients with HFrEF. Therefore, assessing for reversal of EOV as a gauge of therapeutic efficacy can be useful in the clinical and research setting.
Class IIa
B
˙ O2, may be responsive to pharmacologic, Primary CPX variables, including the VE/VCO2 slope and peak V ˙ O2 surgical, and exercise interventions in patients with HFpEF. As such, the VE/VCO2 slope and peak V can be useful as core variables when gauging therapeutic efficacy in patients with HFpEF in both the clinical and research setting.
Class IIa
C
Class IIb
B
Prognostic recommendations CPX should be performed in patients with HFrEF being considered for heart transplantation or mechanical device implantation. However, CPX provides robust prognostic information in all patients with HFrEF and therefore is recommended in those not being considered for end-stage surgical management. ˙ O2, and EOV, are strong predictors of adverse events. Primary CPX variables, including the VE/VCO2 slope, peak V The response of these three CPX variables is recommended to form the basis of the prognostic assessment in patients ˙ O2 e 10 mLO2&kgj1&minj1, and the presence with HFrEF. A combination of a VE/VCO2 slope Q45.0, peak V of EOV carries a particularly poor prognosis.
Recommendations for gauging therapeutic efficacy ˙ O2, are responsive to numerous pharmacologic, Primary CPX variables, including the VE/VCO2 slope and peak V surgical, and exercise interventions in patients with HFrEF. As such, assessment of the change in the VE/VCO2 ˙ O2 is recommended when gauging therapeutic efficacy in patients with HFrEF in both the clinical slope and peak V and research setting.
Diagnostic recommendations CPX variables reflecting ventilatory efficiency, including the VE/VCO2 slope, EOV, and PETCO2 at rest and during exercise may be considered in detecting left-sided PH in patients with HFrEF and HFpEF. If all three of these variables are in their respective red zones, as illustrated in the Figure, the suspicion that the patient has left-sided PH may be reasonable. A primary indication of CPX for diagnostic purposes cannot be recommended at this time. Diagnostic assessments may be considered in patients with HF referred for CPX for prognostic evaluation or assessment of therapeutic efficacy.
CPX indicates cardiopulmonary exercise testing; ECG, electrocardiogram; EOV, exercise oscillatory ventilation; HFrEF, heart failure reduced ejection fraction; HFpEF, heart failure preserved ejection fraction; PETCO2, partial pressure of end-tidal carbon dioxide; PH, pulmonary hypertension; VE/VCO2, minute venti˙ O2, oxygen consumption. lation/carbon dioxide production; V
by the AHA/ACC have provided guidance on class recommendations and levels of evidence for CPX in patients with HF in a narrowly focused fashion. Given the new CPX paradigm proposed that is supported strongly by research in this article, revision to and expansion of class recommendations and associated levels of evidence is warranted. It is clear that several application-specific class recommendations and associated levels of evidence are appropriate. The authors propose that a primary prognostic recommendation for CPX be restored to a Class I recommendation at a level of evidence ‘‘A’’ for three primary variables in patients with HFrEF: 1) The ˙ O2. The body of VE/VCO2 slope, 2) EOV, and 3) peak V evidence clearly justifies this recommendation. There are Volume 42 & Number 4 & October 2014
numerous other indications and considerations for CPX that expand its utility. It is our hope that the CPX paradigm proposed herein, supported by a robust evidence base, increases appropriate utilization of this exercise assessment, improves patient care, and stimulates the future research needed to revise several of the newly proposed class recommendations and associated levels of evidence more definitively. Acknowledgments The authors acknowledge the significant contributions to the body of literature pertaining to CPX in HF that could not be cited because of reference limitations. CPX in Heart Failure
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References 1. Arena R, Guazzi M, Myers J, Ann PM. Prognostic characteristics of cardiopulmonary exercise testing in heart failure: comparing American and European models. Eur. J. Cardiovasc. Prev. Rehabil. 2005; 12(6):562Y7. 2. Arena R, Guazzi M, Myers J, Grinnan D, Forman DE, Lavie CJ. The emerging role of cardiopulmonary exercise testing in the assessment of suspected or confirmed pulmonary arterial hypertension and secondary pulmonary hypertension. Exp. Rev. Respir. Med. 2011; 5:281Y93. 3. Arena R, Myers J, Abella J, Peberdy MA, Bensimhon D, Chase P, Guazzi M. Development of a ventilatory classification system in patients with heart failure. Circulation. 2007; 115(18):2410Y7. 4. Arena R, Myers J, Abella J, Peberdy MA, Bensimhon D, Chase P, Guazzi M. The prognostic value of the heart rate response during exercise and recovery in patients with heart failure: influence of beta-blockade. Int. J. Cardiol. 2010; 138(2):166Y73. 5. Arena R, Myers J, Abella J, et al. Defining the optimal prognostic window for cardiopulmonary exercise testing in patients with heart failure. Circ. Heart Fail. 2010; 3(3):405Y11. 6. Arena R, Myers J, Aslam S, Varughese EB, Peberdy MA. Technical considerations related to the minute ventilation/carbon dioxide output slope in patients with heart failure. Chest. 2003; 124(2):720Y7. ˙ O2 and 7. Arena R, Myers J, Aslam SS, Varughese EB, Peberdy MA. Peak V the VE/VCO2 slope in patients with heart failure: a prognostic comparison. Am. Heart J. 2004; 147(2):354Y60. 8. Arena R, Myers J, Guazzi M. The clinical and research applications of aerobic capacity and ventilatory efficiency in heart failure: an evidencebased review. Heart Fail. Rev. 2008; 13(2):245Y69. 9. Arena RA, Guazzi M, Myers J, Abella J. The prognostic value of ventilatory efficiency with beta-blocker therapy in heart failure. Med. Sci. Sports Exerc. 2007; 39(2):213Y9. 10. Arena R, Guazzi M, Myers J. Prognostic value of end-tidal carbon dioxide during exercise testing in heart failure. Int. J. Cardiol. 2007; 117(1):103Y8. 11. Arena R, Guazzi M, Myers J, Peberdy MA. Prognostic value of heart rate recovery in patients with heart failure. Am. Heart J. 2006; 151(4):851. 12. Arena R, Myers J, Abella J, Peberdy MA. Influence of heart failure etiology on the prognostic value of peak oxygen consumption and minute ventilation/ carbon dioxide production slope. Chest. 2005; 128(4):2812Y7. 13. Arena R, Myers J, Abella J, et al. The partial pressure of resting end-tidal carbon dioxide predicts major cardiac events in patients with systolic heart failure. Am. Heart J. 2008; 156(5):982Y8. 14. Arena R, Myers J, Guazzi M. Cardiopulmonary exercise testing is a core assessment for patients with heart failure. Congest. Heart Fail. 2011; 17(3):115Y9. 15. Balady GJ, Arena R, Sietsema K, et al. Clinician’s guide to cardiopulmonary exercise testing in adults. A scientific statement from the American Heart Association. Circulation. 2010; 122(2):191Y225. 16. Cahalin LP, Chase P, Arena R, et al. A meta-analysis of the prognostic significance of cardiopulmonary exercise testing in patients with heart failure. Heart Fail. Rev. 2013; 18(1):79Y94. 17. Chase P, Arena R, Myers J, et al. Relation of the prognostic value of ventilatory efficiency to body mass index in patients with heart failure. Am. J. Cardiol. 2008; 101(3):348Y52. 18. Chase P, Arena R, Myers J, et al. Prognostic usefulness of dyspnea versus fatigue as reason for exercise test termination in patients with heart failure. Am. J. Cardiol. 2008; 102(7):879Y82. 19. Gibbons RJ, Balady GJ, Beasley JW, et al. ACC/AHA guidelines for exercise testing. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Exercise Testing). J. Am. Coll. Cardiol. 1997; 30(1):260Y311. 20. Gibbons RJ, Balady GJ, Timothy BJ, et al. ACC/AHA 2002 guideline update for exercise testing: summary article. A report of the American College of Cardiology/American Heart Association Task Force on Prac-
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Revisiting Cardiopulmonary Exercise Testing Applications in Heart Failure: Aligning Evidence with Clinical Practice Ross Arena 1, Marco Guazzi 2, Lawrence P. Cahalin 3, and Jonathan Myers 4 1
Department of Physical Therapy and Integrative Physiology Laboratory, College of Applied Health Sciences, University of Illinois Chicago, Chicago, IL; 2Heart Failure Unit, Cardiology, University of Milano, IRCCS Policlinico San Donato, Milano, Italy; 3Department of Physical Therapy, Leonard M. Miller School of Medicine, University of Miami, Miami, FL; and 4Division of Cardiology, VA Palo Alto Healthcare System, Palo Alto, CA. ARENA, R., M. GUAZZI, L.P. CAHALIN, and J. MYERS. Revisiting cardiopulmonary exercise testing applications in heart failure: aligning evidence with clinical practice. Exerc. Sport Sci. Rev., Vol. 42, No. 4, pp. 153Y160, 2014. American Heart Association/ American College of Cardiology class recommendations and associated level of evidence for cardiopulmonary exercise testing (CPX) have been put forth. A new paradigm is proposed for CPX use and interpretation in heart failure (HF). Evidence for this new paradigm will be provided, showing that clinical utilization, class recommendations, and the associated level of evidence for CPX in the HF population can be expanded significantly. Key Words: exercise testing, expired gas, prognosis, diagnosis, class recommendation, level of evidence
Editor’s note: Go online to view the Journal Club questions in the Supplemental Digital Content: see http://links.lww.com/ESSR/A9.
plantation.’’ There was no associated level of evidence with this recommendation (19,20). The more recent HF-specific clinical guideline (2005 and 2009 update) changed the recommendation for CPX to Class IIa (i.e., ‘‘indicates that the weight of evidence/opinion is in favor of usefulness/efficacy’’) as ‘‘being reasonable to identify high-risk patients presenting with HF who are candidates for cardiac transplantation or other advanced treatments’’ (32). The level of evidence associated with this recommendation was ‘‘B’’ (i.e., ‘‘a limited number of randomized controlled trials with small numbers of studies or observational registries’’). No rationale was provided for the change in CPX class recommendation (i.e., from I to IIa). Despite the change in class recommendation, CPX utilization in patients with HF has been viewed, at least in concept, as a widely available clinical standard of care for more than a decade (15). There are several caveats to previous CPX class recommendation and level of evidence designations that may not be readily apparent: 1) The reason CPX continues to be considered valuable in patients with HF who are being considered for heart transplantation or other advanced treatments is because of the assumption that this procedure provides a robust ability to predict adverse events, in particular, mortality. During the last decade, the value of CPX in predicting mortality in HF has been confirmed consistently by numerous observational studies, even in cohorts not being considered for transplantation or other advanced treatments. However, the view of the prognostic and, therefore, primary
INTRODUCTION The American Heart Association (AHA) and the American College of Cardiology (ACC) use a rigorous system for determining class recommendation and associated level of evidence for practice patterns, serving as the basis for their clinical guidelines. A detailed description of this system is provided elsewhere (21). The AHA/ACC has used this class recommendation/level of evidence system for the use of cardiopulmonary exercise testing (CPX) in patients with heart failure (HF). Initial guidance (1997 and 2002 update) afforded CPX a Class I recommendation (i.e., ‘‘conditions for which there is evidence or general agreement that a given procedure or treatment is useful and effective’’) for the ‘‘evaluation of exercise capacity and response to therapy in patients with HF who are being considered for heart trans-
Address for correspondence: Ross Arena, Ph.D., P.T., FAHA, Department of Physical Therapy, College of Applied Health Sciences, University of Illinois Chicago, 1919 W. Taylor St. (MC 898), Chicago, IL 60612 (E-mail: [email protected]). Accepted for publication: May 5, 2014. Associate Editor: Bo Fernhall, Ph.D., FACSM 0091-6331/4204/153Y160 Exercise and Sport Sciences Reviews Copyright * 2014 by the American College of Sports Medicine
153 Copyright © 2014 by the American College of Sports Medicine. Unauthorized reproduction of this article is prohibited.
clinical utility of CPX remains narrowly focused on those being considered for end-stage interventions (e.g., transplantation); 2) In both previous AHA/ACC clinical practice guidelines and their revisions, peak oxygen consumption ˙ O2) was the only variable considered for the assessment of (V transplant candidacy, advanced treatments, or gauging therapeutic efficacy V despite the fact that a host of other potentially valuable CPX variables are readily obtainable; and 3) Given that heart transplantation continues to be reserved for patients diagnosed as having HF and reduced ejection fraction (HFrEF), the recommendations provided in these clinical guidelines were meant to apply exclusively to this subgroup. Thus, none of the CPX proposed recommendations provided in these guidelines apply to patients with HF and preserved ejection fraction (HFpEF). The body of scientific evidence and perceived clinical utility and value of CPX currently are incongruent. Stated succinctly, previous clinical practice ˙ O2 is the guidelines perpetuate the following premise: Peak V only CPX variable that holds prognostic value, only in patients with HFrEF. Scientific evidence, however, indicates that the value and clinical applications of CPX in the HF population are much richer and broader, respectively. There have been many advances in the years since the 1997 and 2002 updates to the AHA/ACC Guidelines for Exercise Testing were published (19,20). The same can be said for the 2005 and 2009 updates to the guidelines for HF diagnosis and management (32). The clinical, pharmacologic, and surgical management of the HF population continues to expand and evolve, and, although prognosis in this chronic disease population remains disconcerting, it has improved substantially. Moreover, the unique pathophysiology, presentation, and clinical trajectory of patients diagnosed with HFrEF as compared with those with HFpEF are being recognized increasingly. Lastly, the body of evidence investigating the clinical utility of CPX with respect to prognostic, diagnostic, and therapeutic efficacy assessments continues to increase. As such, a new paradigm for CPX use and interpretation in HF is warranted. We hypothesize that scientific evidence for this new paradigm is substantial, proving that clinical utilization, class recommendations, and the associated level of evidence for CPX in the HF population can be expanded significantly. Our group initiated a multicenter consortium in 2002 in an effort to gain better insights into the role of CPX in HF. Combining data from established centers allow important hypotheses to be tested with an appropriate sample size (currently n 9 2500) and, thus, statistical power (36). The multicenter consortium has contributed significantly to the worldwide body of work related to CPX utility in HF (22). The collective body of available evidence supports the hypothesis that a new CPX paradigm is warranted, one that involves: 1) expanding the list of relevant CPX variables based on scientific evidence; 2) incorporating diagnostic, prognostic, and therapeutic efficacy applications; and 3) expanding utilization of CPX beyond patients with HFrEF being considered for heart transplantation. Many of the studies discussed in subsequent sections of this article focus on results from the multicenter consortium, lending support to the hypothesis that a new CPX paradigm in HF is justifiable. Updated/revised/expanded class 154 Exercise and Sport Sciences Reviews
recommendations and associated levels of evidence will be presented with the following questions in mind: 1) Does CPX continue to provide prognostic value in patients with HF? 2) Would there be value to expanding the clinical applications of CPX to all patients with HF, as opposed to only those being evaluated actively for transplantation? 3) Should the list of CPX variables for prognostic assessment be expanded ˙ O2? 4) Are key CPX variables responsive to beyond peak V various interventions, allowing for a valid and reliable gauge of therapeutic efficacy? 5) What CPX variables(s) should be included in the assessment of therapeutic efficacy? 6) Are there diagnostic applications for CPX in patients with HF? and 7) Should CPX be used clinically in both the HFrEF and HFpEF populations?
CURRENT APPRAISAL OF THE PROGNOSTIC VALUE OF CPX In 1991, Mancini et al. (34) published their seminal work ˙ O2 in a group of 114 patients on the predictive value of peak V with HFrEF, demonstrating its significant prognostic ability. Since that time and for reasons that are not clear, a narrow and limited clinical view of the prognostic value of CPX perpetuates, despite the fact that evidence continues to mount in support of a new broader paradigm. The multicenter consortium has published a number of analyses related to the prognostic value of CPX, supporting the hypothesis that a new broader prognostic paradigm is warranted. The consortium’s work reaffirms the prognostic ˙ O2 as well as significantly contributes to the value of peak V rationale of expanding the prognostic assessment to other CPX variables based on sound physiologic rationale for why they may be relevant clinically. There is a specific interest in ventilatory efficiency, in particular, expressed as the minute ventilation per carbon dioxide production (VE/VCO2) slope. The multicenter consortium demonstrated that the VE/VCO2 slope portended an optimal prognostic value when all exercise testing data are used (i.e., from the initiation of the CPX to the attainment of maximal effort) (6), a finding subsequently supported by other research groups. A number of other consortium publications demonstrate that both the VE/VCO2 ˙ O2 are robust prognostic markers in patients slope and peak V ˙ O2 with HFrEF (1,3,8,9,12). However, although both peak V and the VE/VCO2 slope are significant prognostically, the latter is more robust in univariate analyses (3,7,8,16), a finding also supported by other research groups. However, both variables oftentimes remain significant prognostically in a multivariate model. In 2007, the consortium introduced a ventilatory classification system based on the VE/VCO2 slope (3). During the same period, the emergence of the beta-blocker era and ˙ O2 with a concomitant improveits neutral impact on peak V ment in survival precipitated reconsideration of the less than or equal to/greater than 14 mLO2&kgj1&minj1 prognostic threshold. Indeed, a threshold of less than/greater than or equal to 10 mLO2&kgj1&minj1 was suggested to be more appropriate in HFrEF patients prescribed a beta-blocker (37). With respect to the VE/VCO2 slope, it seemed that patients with a value greater than or equal to 45 (normal value G30) had a particularly poor prognosis (3). As the body of literature evolved, it www.acsm-essr.org
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was proposed that patients with a VE/VCO2 slope greater than ˙ O2 less than 10 mLO2&kgj1&minj1 or equal to 45 and peak V had a particularly poor prognosis and should be considered to be at extremely high risk for adverse events (i.e., estimated to be 950%) (14). Moreover, for HFrEF patients with a VE/ ˙ O2 below and above these ominous VCO2 slope and peak V thresholds, respectively, prognostic outlook improved progressively, with a multilevel model being the best approach to risk assessment. For patients with a VE/VCO2 slope less than 30 ˙ O2 greater than 20 mlO2&kgj1&minj1, prognosis is and peak V considered excellent, at least during the next 2 to 4 yr. This was the beginning of an expanded view of CPX variables for prognostic analysis and a new paradigm, combining the VE/ ˙ O2 response. VCO2 slope and the peak V Further growth of the multicenter HF consortium CPX database prompted exploration of the additive prognostic value of other CPX variables; both those obtained from ventilatory expired gas and traditional monitoring (i.e., heart rate, blood pressure, and subjective symptoms), further evolving the new paradigm. Exercise oscillatory ventilation (EOV) (26), the partial pressure of end-tidal CO2 (PETCO2) at rest and during exercise (10,13), heart rate recovery (HRR) (4,11), and dyspnea as a test termination criteria (18) are all prognostically significant in patients with HF, supporting the hypothesis that an expanding prognostic CPX paradigm portends an improved three-dimensional resolution in predicting adverse events. The demonstrated prognostic ability of all aforementioned CPX variables is grounded in the fact that each provides a unique reflection of the degree of pathophysiology present in one or more of the systems influencing the response to aerobic exercise (i.e., pulmonary/respiratory, cardiovascular, skeletal muscle). A discussion of the link between CPX measures and pathophysiology is beyond the scope of this article; other excellent resources addressing this issue are available (15). The multicenter consortium recently proposed a CPX score incorporating the majority of these variables (35), which was validated recently in a subsequent publication (36). Other research groups that have assessed large HF cohorts have demonstrated similar findings regarding the prognostic value of the aforementioned CPX variables. In 2012, the AHA and European Association for Cardiovascular Prevention and Rehabilitation jointly published the Clinical Recommendations for Cardiopulmonary Exercise Testing Data Assessment for Specific Patient Populations, including HF (22). This joint statement recommends that the VE/VCO2 ˙ O2, EOV, PETCO2, systolic blood pressure reslope, peak V sponse, exercise electrocardiography, HRR, and subjective symptom exercise termination criteria be assessed collectively for a more refined prognostic assessment. This color-coded prognostic model is illustrated in the Figure. This new paradigm represents the current best-practice recommendation for the interpretation of CPX data for prognostic purposes in the HF population. This new paradigm is supported strongly by evidence, reflecting a body of literature that collectively has assessed the prognostic value of CPX in thousands of patients with HF, with strong consistency in findings among the different research groups around the world. As such, we feel that the evidence-based model illustrated in the Figure is an excellent example of the vision for a new CPX paradigm that this article has set out to propose. Volume 42 & Number 4 & October 2014
CPX AS A GAUGE FOR THERAPEUTIC EFFICACY Although the original AHA/ACC Guidelines for Exercise Testing also afforded CPX a Class I recommendation to gauge the ‘‘response to therapy in patients with HF who are being considered for heart transplantation,’’ its use in this capacity is not commonplace clinically. This approach entails serial CPX testing before and after the implementation of a given intervention. Use of CPX as a gauge for therapeutic efficacy aligns with the prognostic applications previously described; if a given intervention improves the CPX response, it is reasonable to hypothesize that prognosis likewise improves. Given the robust prognostic value of CPX, in particular using the newly proposed multivariable paradigm illustrated in the Figure, assessing the change in key variables after the initiation or titration of a given intervention potentially would be of high value in guiding clinical management. The concept of serial CPX was reinforced in the 2007 multicenter consortium paper introducing the Ventilatory Classification System (3). Specifically, in patients with an abnormal VE/VCO2 slope, reviewing and titrating medical management are recommended. When medical management is titrated, repeating CPX to assess therapeutic efficacy is proposed. Other publications have demonstrated significant improvements in key CPX variables, most notably the VE/VCO2 slope and peak ˙ O2, after numerous intervention strategies (23). Moreover, V a reduction in pulmonary artery pressure after treatment with sildenafil, a phosphodiesterase 5 inhibitor, significantly correlates with the reduction in the VE/VCO2 slope (25). It also seems that treatment with sildenafil reverses EOV (31). In addition, an interleukin 1 receptor antagonist trial initially ˙ O2 has demonstrated significant improvements in peak V and the VE/VCO2 slope in patients with HFrEF after this pharmacologic intervention (38). These studies convincingly demonstrate that CPX is a valuable tool in indentifying responders versus nonresponders to a given therapeutic intervention, recalibrating prognostic outlook based on therapeutic responsiveness, and further titrating clinical management based on the level of responsiveness as reflected by the change in CPX. Physiologic mechanisms for the improvement in CPX variables are based uniquely on a specific therapeutic intervention (e.g., the reduction in the VE/VCO2 slope with sildenafil is related to the concomitant reduction in pulmonary pressure and subsequent improvement in ventilation-perfusion matching). In conclusion, the research findings described in this section support the premise that multiple CPX variables respond favorably to interventions that have a positive physiologic impact on the cardiovascular and/or pulmonary systems. Thus, assessing therapeutic CPX improvements through the new multivariate paradigm illustrated in the Figure is warranted.
THE DIAGNOSTIC APPLICATIONS OF CPX The diagnostic applications of CPX in patients with HF previously have not been afforded a class recommendation and associated level of evidence designation in the AHA/ ACC clinical practice guidelines. Admittedly, CPX as a tool to determine an initial diagnosis of HF would not be warranted because a number of other chronic conditions produce CPX in Heart Failure
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Figure. Clinical CPX stratification for patients with HF. (Reprinted from (22). Copyright * 2012 American Heart Association. Used with permission.) *Peak V˙O2 valid if peak RER is Q1.00 or test terminated secondary to abnormal hemodynamic or ECG exercise response. VE/VCO2 indicates minute ventilation/carbon dioxide production; V˙O2, oxygen consumption; EOV, exercise oscillatory ventilation; PETCO2, partial pressure of end-tidal carbon dioxide; ET, exercise test; ECG, electrocardiogram; HRR, heart rate recovery; BP, blood pressure; CPX, cardiopulmonary exercise testing; HF, heart failure; PH, pulmonary hypertension; RER, respiratory exchange ratio.
similar CPX abnormalities (e.g., pulmonary arterial hypertension, congenital heart defects, and interstitial lung disease). However, the use of CPX to aid in the diagnosis of secondary pathophysiologic consequences of HF seems appropriate and clinically valuable, in particular, left-sided pulmonary hypertension (PH) (28). Ventilatory inefficiency, as expressed by an elevated VE/VCO2 slope, possesses the ability to diagnose left-sided PH noninvasively with acceptable sensitivity/specificity and positive/negative predictive values. 156 Exercise and Sport Sciences Reviews
The pathophysiologic rationale for this relationship is the fact that increased pulmonary pressure creates a greater ventilationperfusion mismatch, reflected by an elevated VE/VCO2 slope. Moreover, there seems to be a significant correlation between the severity of PH (i.e., degree of rise in pulmonary artery pressure) and the degree of elevation in the VE/VCO2 slope; thus, the latter seems to provide a noninvasive reflection of disease severity. As described in the review by Arena et al. (2), the majority of the literature supporting this premise has been www.acsm-essr.org
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performed in cohorts diagnosed as having primary pulmonary vascular disease. However, Guazzi et al. recently demonstrated that the VE/VCO2 slope (threshold G/Q36, odds ratio = 12.1, P G 0.001) was the strongest predictor of an elevated pulmonary artery systolic pressure (Q40 mmHg), assessed by Doppler echocardiography, in an HF cohort (n = 293). Peak exercise PETCO2 (threshold e/936 mmHg, odds ratio = 3.8, P G 0.001) and EOV (yes vs. no, odds ratio = 3.2, P G 0.001), CPX variables that also reflect ventilatory inefficiency, improved the ability to detect an elevated pulmonary artery systolic pressure (odds ratio for all three variables combined = 16.7, P G 0.001). Thus, although CPX is not viewed as an assessment that holds value in confirming an HF diagnosis, it does hold value in diagnosing secondary consequences of HF, namely, left-sided PH. Moreover, although CPX is valuable in accurately detecting left-sided PH, the authors of this review do not recommend it should be viewed as the test that would confirm such a diagnosis. Rather, if the CPX response is strongly suggestive of left-sided PH in patients with HF (i.e., indicators of ventilatory efficiency), an appropriate next step would be to consider a follow-up assessment to confirm the initial impression, such as Doppler echocardiography or right heart catheterization.
UNIQUE CONSIDERATIONS FOR THE APPLICATION OF CPX IN HF As discussed in the Introduction, a primary and currently underexamined issue related to this focus is exploring the clinical value of CPX in patients diagnosed as having HFpEF. The multicenter consortium has examined the value of CPX in patients diagnosed as having HFpEF, supporting key facets of the newly proposed paradigm by demonstrating 1) a significant correlation between key CPX variables (i.e., peak ˙ O2, the VE/VCO2 slope, resting and exercise PETCO2) and V diastolic dysfunction, as assessed by Doppler echocardiography (i.e., E/E¶) (24); and 2) the prognostic significance of the
VE/VCO2 slope and EOV in patients with HFpEF (29,30). The multicenter consortium also has addressed other unique considerations in the CPX-HF literature, demonstrating 1) an interplay between the obesity paradox and the preserved ˙ O2 and the VE/VCO2 slope prognostic value of peak V (17,33); 2) the preserved prognostic value of CPX irrespective of both sex (27) and HF etiology (12); and 3) a 2- to 4-yr ˙ O2 and the VE/ window for the prognostic validity of peak V VCO2 slope, after which time a repeat assessment may be warranted (5).
CPX CLASS RECOMMENDATIONS AND ASSOCIATED LEVELS OF EVIDENCE It has been several years since the AHA/ACC class recommendations and associated levels of evidence have been reviewed for CPX in HF. Initially, CPX was afforded a Class I recommendation with no associated level of evidence in the AHA/ACC Guidelines for Exercise Testing (19). Moreover, the scope of the recommendation was rather narrow with respect to CPX variables assessed and the type of HF patients undergoing CPX (i.e., heart transplant candidates and HFrEF). The 2005 guidelines for the diagnosis and management of HF in adults revisited recommendations for CPX; changing the recommendation to Class IIa with an associated ‘‘B’’ level of evidence. To our knowledge, no rationale, evidence based or otherwise, was provided for this change in recommendation class. During this same time, the body of CPX literature has expanded exponentially, warranting reexamination of this issue. Our current assessment of this area allowed for several key observations to be made as a part of our newly proposed paradigm: 1) The AHA/ACC Class Recommendation/Level of Evidence System does not have language that describes specifically how to provide recommendations for or rate levels of evidence related to prognostic assessments; 2) The CPX body of literature in HF has expanded to a point where a more refined and detailed approach to class recommendation
TABLE 1. Broad language and concept guidance for CPX class recommendations. Class I
Class IIa
Class IIb
Class III
CPX is clearly prognostic/diagnostic
CPX is likely prognostic/diagnostic
CPX may be prognostic/diagnostic
CPX is not prognostic/diagnostic
CPX clearly gauges therapeutic efficacy
CPX likely gauges therapeutic efficacy
CPX may gauge therapeutic efficacy
CPX does not gauge therapeutic efficacy
CPX:
CPX:
CPX:
CPX:
- Should be performed
- Is probably recommended
- May be considered
- Has no benefit
- Is recommended
- Is probably indicated
- May be reasonable
- Is not recommended
- Is indicated
- Can be useful
- Usefulness is unknown
- Is not indicated
- Is useful
- Can be effective
- Usefulness is unclear
- Should not be performed
- Is effective
- Can be beneficial
- Usefulness is uncertain
- Should not be administered
- Is beneficial
- Usefulness is not well established
- Is not useful - Is not beneficial - Is not effective
CPX indicates cardiopulmonary exercise testing. Volume 42 & Number 4 & October 2014
CPX in Heart Failure
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157
TABLE 2. Broad language and concept guidance for CPX level of evidence ratings. Study Characteristics Level A
Study Findings
- Multiple investigations, possibly one or more meta-analyses
Results from overall body of evidence and meta-analyses (if available) consistently demonstrate similar findings.
- Prospective design
Sum of results from all studies allow for definitive conclusions without the need for further inquiry.
- Hard end point (mortality) collected in standardized and rigorous fashion for prognostic studies - Interventional trials using CPX as an end point used randomized controlled design - Recognized gold standard used as CPX comparator for diagnostic studies - Prognostic, interventional, and diagnostic studies consistently demonstrate rigorous research design, appropriate statistical tests, and sufficiently powered Level B
- Several investigations; total number of studies not considered definitive because of total number and/or study quality
Results from overall body of evidence may not consistently demonstrate similar findings. Sum of results from all studies do not allow for definitive conclusion, and further inquiry is needed.
- Mix of prospective and retrospective study designs - Mix of hard end point (i.e., mortality) and softer end point (i.e., hospitalization) collected in standardized but less rigorous fashion for prognostic studies - Interventional trials using CPX as an end point used mix of case control, cohort, and randomized controlled designs - CPX comparator for diagnostic studies not always been recognized gold standard - Prognostic, interventional, and diagnostic studies may present with limitations in research design rigor, appropriate statistical tests, and/or sufficient power Level C
- Scientific evidence, if any available, limited - Rely on consensus opinion of experts
Results from body of evidence, if available, not sufficient to draw any conclusions on consistency of findings. Studies from other areas may be used to derive expert opinion. Significant further inquiry is needed.
CPX indicates cardiopulmonary exercise testing.
and associated level of evidence is justified. These observations serve as the genesis of the new conceptual framework provided in Tables 1 to 3. Tables 1 and 2 provide guidance on class recommendation and levels of evidence language and concepts. These tables are constructed with the intent of being applicable to all areas relevant to CPX (i.e., prognosis, therapeutic efficacy, and diagnosis). The language and concepts presented in Tables 1 and 2 form the basis for the proposed CPX class recommendations and associated levels of evidence for prognostic, therapeutic efficacy, and diagnostic applications in the HF population, which are listed in Table 3. Based on the body of literature, the number of CPX variables that should be considered, the variation in how extensively each individual variable has been studied currently, and the number of potential CPX indications in the clinical and research settings, a more refined and extensive list of class recommendations and levels of evidence is ˙ O2, the VE/ warranted. With respect to prognosis, peak V VCO2 slope, and EOV are primary CPX markers with clear predictive values. Other variables add predictive values, and thus, a multivariate predictive model is appropriate. These recommendations are well established in patients with HFrEF. Initial prognostic analyses of CPX in patients with HFpEF 158 Exercise and Sport Sciences Reviews
shows promise but is more guarded, given that more research ˙ O2 are is needed in this area. The VE/VCO2 slope and peak V primary variables for gauging therapeutic efficacy, a premise well supported by the literature in patients with HFrEF. There also are some indications that reversal of EOV may occur with certain therapeutic interventions in patients with HFrEF, highlighting the important role this prognostic marker seems to have in clinical practice. In general, however, the use of CPX to gauge therapeutic efficacy in patients with HFpEF needs further inquiry. Lastly, the diagnostic utility of CPX may be useful in the overall HF population, in particular, the ability of abnormalities in ventilatory efficiency to detect leftsided PH. Additional research is needed to solidify the diagnostic value of CPX in HF.
CONCLUSIONS The current concept paper set out to test the hypothesis that a new and expanded paradigm for CPX application and interpretation in HF is warranted. The current body of research, significantly contributing to by the multicenter consortium, supports this paradigm. Clinical guidelines published www.acsm-essr.org
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TABLE 3. Class recommendation and level of evidence for CPX in heart failure. Recommendation
Classification
Level of Evidence
Class I
A
Secondary CPX variables, including PETCO2, ECG, systolic blood pressure, and the ECG response to exercise, are additional predictors of adverse events and can be useful during the prognostic assessment in patients with HFrEF. A resting PETCO2 G33 mmHg, a rise in PETCO2 G3 mmHg during exercise, a drop in systolic blood pressure during exercise, and/or ECG abnormalities warranting termination of exercise indicate a worse prognosis.
Class IIa
B
Use of a multivariate model composed of key CPX variables and thresholds, as illustrated in the Figure, can be useful in improving prognostic resolution in patients with HFrEF in comparison with variables assessed independently.
Class IIa
B
The prognostic value of patients with HFpEF is showing initial promise, in particular, the VE/VCO2 slope, ˙ O2, and EOV. These variables can be useful in providing prognostic information in patients with HFpEF. peak V
Class IIa
B
Use of a multivariate model composed of key CPX variables and thresholds, as illustrated in the Figure, can be useful in improving prognostic resolution in patients with HFpEF in comparison with variables assessed independently.
Class IIa
C
Class I
A
Reversal of EOV also may occur with pharmacologic, surgical, and exercise interventions in patients with HFrEF. Therefore, assessing for reversal of EOV as a gauge of therapeutic efficacy can be useful in the clinical and research setting.
Class IIa
B
˙ O2, may be responsive to pharmacologic, Primary CPX variables, including the VE/VCO2 slope and peak V ˙ O2 surgical, and exercise interventions in patients with HFpEF. As such, the VE/VCO2 slope and peak V can be useful as core variables when gauging therapeutic efficacy in patients with HFpEF in both the clinical and research setting.
Class IIa
C
Class IIb
B
Prognostic recommendations CPX should be performed in patients with HFrEF being considered for heart transplantation or mechanical device implantation. However, CPX provides robust prognostic information in all patients with HFrEF and therefore is recommended in those not being considered for end-stage surgical management. ˙ O2, and EOV, are strong predictors of adverse events. Primary CPX variables, including the VE/VCO2 slope, peak V The response of these three CPX variables is recommended to form the basis of the prognostic assessment in patients ˙ O2 e 10 mLO2&kgj1&minj1, and the presence with HFrEF. A combination of a VE/VCO2 slope Q45.0, peak V of EOV carries a particularly poor prognosis.
Recommendations for gauging therapeutic efficacy ˙ O2, are responsive to numerous pharmacologic, Primary CPX variables, including the VE/VCO2 slope and peak V surgical, and exercise interventions in patients with HFrEF. As such, assessment of the change in the VE/VCO2 ˙ O2 is recommended when gauging therapeutic efficacy in patients with HFrEF in both the clinical slope and peak V and research setting.
Diagnostic recommendations CPX variables reflecting ventilatory efficiency, including the VE/VCO2 slope, EOV, and PETCO2 at rest and during exercise may be considered in detecting left-sided PH in patients with HFrEF and HFpEF. If all three of these variables are in their respective red zones, as illustrated in the Figure, the suspicion that the patient has left-sided PH may be reasonable. A primary indication of CPX for diagnostic purposes cannot be recommended at this time. Diagnostic assessments may be considered in patients with HF referred for CPX for prognostic evaluation or assessment of therapeutic efficacy.
CPX indicates cardiopulmonary exercise testing; ECG, electrocardiogram; EOV, exercise oscillatory ventilation; HFrEF, heart failure reduced ejection fraction; HFpEF, heart failure preserved ejection fraction; PETCO2, partial pressure of end-tidal carbon dioxide; PH, pulmonary hypertension; VE/VCO2, minute venti˙ O2, oxygen consumption. lation/carbon dioxide production; V
by the AHA/ACC have provided guidance on class recommendations and levels of evidence for CPX in patients with HF in a narrowly focused fashion. Given the new CPX paradigm proposed that is supported strongly by research in this article, revision to and expansion of class recommendations and associated levels of evidence is warranted. It is clear that several application-specific class recommendations and associated levels of evidence are appropriate. The authors propose that a primary prognostic recommendation for CPX be restored to a Class I recommendation at a level of evidence ‘‘A’’ for three primary variables in patients with HFrEF: 1) The ˙ O2. The body of VE/VCO2 slope, 2) EOV, and 3) peak V evidence clearly justifies this recommendation. There are Volume 42 & Number 4 & October 2014
numerous other indications and considerations for CPX that expand its utility. It is our hope that the CPX paradigm proposed herein, supported by a robust evidence base, increases appropriate utilization of this exercise assessment, improves patient care, and stimulates the future research needed to revise several of the newly proposed class recommendations and associated levels of evidence more definitively. Acknowledgments The authors acknowledge the significant contributions to the body of literature pertaining to CPX in HF that could not be cited because of reference limitations. CPX in Heart Failure
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